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A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome

Primary Purpose

Non-transfusion-dependent Thalassemia, Low Risk Myelodysplastic Syndrome, Very-Low Risk Myelodysplastic Syndrome

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
SLN124
Placebo
Sponsored by
Silence Therapeutics plc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-transfusion-dependent Thalassemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult with alpha- or beta-thalassaemia or compound heterozygous haemoglobin E/beta-thalassaemia or adult with very low- or low-risk MDS according to the 2016 revision to the World Health Organisation classification.
  • All subjects must agree to adhere to appropriate contraception requirements.
  • Subjects must provide written informed consent and be able to comply with all study requirements.
  • Body mass index ≥18 kg/m2 and ≤35 kg/m2 at screening.
  • At least one of: a) Mean ferritin >250 μg/L based on a minimum of 2 measurements ≥1 week apart within 20 days before the planned dosing day, in the absence of active significant infection; b) Mean TSAT >40% measured on a minimum of 2 occasions ≥1 week apart within 20 days before the planned dosing day; c) Liver iron >3 mg Fe/g dry weight, measured according to local procedures.
  • Mean baseline haemoglobin concentration ≥5 g/dL and ≤11 g/dL, based on a minimum of 2 measurements ≥1 week apart, within 20 days before the planned dosing day.

Exclusion criteria

  • Adult with haemoglobin S/alpha-thalassaemia or haemoglobin S/beta-thalassaemia or adult with secondary MDS, i.e., MDS that is known to have arisen because of chemical injury or treatment with chemotherapy and/or radiation for another disease.
  • History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc, or intolerance to s.c. injections.
  • Known infection with HIV, or active infectious hepatitis A, B, or C virus.
  • Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrolment in the study or could interfere with the subject's participation in, or completion of the study.
  • History or clinical evidence of alcohol or illegal drug misuse within 2 years before screening.
  • Currently using ESA, or plan to use ESA at any point during the study.
  • Require daily treatment with 1 or more non-steroidal anti-inflammatory drugs during the study period. Paracetamol will be permitted for use as an antipyretic and/or analgesic.
  • Treatment, or change in treatment with prohibited medications as specified in the protocol
  • Treatment with ICT where the subject has not been on a stable dose for at least 8 weeks before screening or it is planned to initiate ICT therapy during the study.
  • Clinically significant cardiac disease
  • Clinically significant pulmonary disease

For subjects with thalassaemia:

  • Treatment, or change in treatment with prohibited medications as specified in the protocol
  • currently and anticipated to receiving more than 5 units of RBCs during the 24 weeks to 6 weeks period before first dose of study drug.

For subjects with very low / low-risk MDS:

  • Previous allogeneic or autologous stem cell transplantation.
  • Currently or planned to receive treatment with a corticosteroid for MDS within 8 weeks before screening.
  • Currently or planned to receive treatment with haematopoietic growth factors (e.g., eltrombopag, romiplostim) within 8 weeks before screening.

Sites / Locations

  • Universitaetsklinikum Duesseldorf
  • Universitat Leipzig
  • Rambam Health Care Campus
  • Sheba Medical Center
  • Tel Aviv Sourasky Medical Center
  • Bar-Ilan University - Faculty of Medicine
  • AUSL della Romagna - Ospedale di Ravenna
  • Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia
  • Jordan University Hospital
  • King Hussein Cancer Center
  • Irbid Speciality Hospital
  • Sarawak General Hospital
  • Hospital Ampang
  • King Chulalongkorn Memorial Hospital
  • Mahidol University - Faculty of Medicine - Ramathibodi Hospital
  • Mahidol University - Siriraj Hospital
  • Faculty of Medicine, Chiang Mai University
  • University Hospital of Wales
  • The Leeds Teaching Hospitals NHS Trust - Saint James's University Hospital
  • Hammersmith Medicines Research Ltd (HMR)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm 15

Arm 16

Arm 17

Arm 18

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Placebo Comparator

Placebo Comparator

Arm Label

1.0mg/kg - Thalassaemia

3.0mg/kg - Thalassaemia

6.0mg/kg - Thalassaemia

Placebo - Thalassaemia

Xmg/kg - Thalassaemia

1.0mg/kg - Myelodysplastic Syndrome

3.0mg/kg - Myelodysplastic Syndrome

10.0mg/kg - Myelodysplastic Syndrome

Xmg/kg - Myelodysplastic Syndrome

3.0mg/kg - Thalassaemia multi dose

10.0mg/kg - Thalassaemia multi dose

Xmg/kg - Thalassaemia multi dose

3.0mg/kg - Myelodysplastic Syndrome multi dose

10.0mg/kg - Myelodysplastic Syndrome multi dose

Xmg/kg - Myelodysplastic Syndrome multi dose

Placebo - Thalassaemia multi dose

Placebo - Myelodysplastic Syndrome

Placebo - Myelodysplastic Syndrome multi dose

Arm Description

Outcomes

Primary Outcome Measures

Incidence of treatment-emergent adverse events
safety and tolerability will be reported separately following single-dose administration.
Incidence of treatment-emergent adverse events
safety and tolerability will be reported separately following multi-dose administration.

Secondary Outcome Measures

Pharmacokinetic: peak plasma concentration (Cmax)
Will be reported separately following single-dose and multiple-dose administration.
Pharmacokinetic: area under the plasma concentration (AUC)
Will be reported separately following single-dose and multiple-dose administration.
Pharmacokinetic: apparent total clearance from plasma after s.c injection (CL/F)
Will be reported separately following single-dose and multiple-dose administration.
Pharmacodynamic biomarkers: Change in TSAT after s.c injection.
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Pharmacodynamic biomarkers: Change in hepcidin after s.c injection.
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Pharmacodynamic biomarkers: Change in serum iron after s.c injection.
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Pharmacodynamic biomarkers: Change in haemoglobin after s.c injection.
safety and tolerability will be reported separately following single-dose and multiple-dose administration.

Full Information

First Posted
January 19, 2021
Last Updated
August 8, 2023
Sponsor
Silence Therapeutics plc
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1. Study Identification

Unique Protocol Identification Number
NCT04718844
Brief Title
A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome
Official Title
A Randomised, Single-blind, Placebo-controlled, Phase 1, Single-ascending and Multiple-dose Study in Adult Subjects With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome to Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 14, 2021 (Actual)
Primary Completion Date
May 23, 2023 (Actual)
Study Completion Date
September 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Silence Therapeutics plc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will investigate the safety and tolerability of SLN124 in patients with Thalassaemia or patients with Very Low- and Low-risk Myelodysplastic Syndrome (MDS) after single ascending s.c. doses and multiple doses in healthy male and female subjects. Up to 7 cohorts of 56 patients with Thalassaemia and up to 7 cohorts of 56 patients with MDS will be enrolled. Each subject will receive single or multiple doses of SLN124 or placebo given by subcutaneous (s.c) injection.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-transfusion-dependent Thalassemia, Low Risk Myelodysplastic Syndrome, Very-Low Risk Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1.0mg/kg - Thalassaemia
Arm Type
Experimental
Arm Title
3.0mg/kg - Thalassaemia
Arm Type
Experimental
Arm Title
6.0mg/kg - Thalassaemia
Arm Type
Experimental
Arm Title
Placebo - Thalassaemia
Arm Type
Placebo Comparator
Arm Title
Xmg/kg - Thalassaemia
Arm Type
Experimental
Arm Title
1.0mg/kg - Myelodysplastic Syndrome
Arm Type
Experimental
Arm Title
3.0mg/kg - Myelodysplastic Syndrome
Arm Type
Experimental
Arm Title
10.0mg/kg - Myelodysplastic Syndrome
Arm Type
Experimental
Arm Title
Xmg/kg - Myelodysplastic Syndrome
Arm Type
Experimental
Arm Title
3.0mg/kg - Thalassaemia multi dose
Arm Type
Experimental
Arm Title
10.0mg/kg - Thalassaemia multi dose
Arm Type
Experimental
Arm Title
Xmg/kg - Thalassaemia multi dose
Arm Type
Experimental
Arm Title
3.0mg/kg - Myelodysplastic Syndrome multi dose
Arm Type
Experimental
Arm Title
10.0mg/kg - Myelodysplastic Syndrome multi dose
Arm Type
Experimental
Arm Title
Xmg/kg - Myelodysplastic Syndrome multi dose
Arm Type
Experimental
Arm Title
Placebo - Thalassaemia multi dose
Arm Type
Placebo Comparator
Arm Title
Placebo - Myelodysplastic Syndrome
Arm Type
Placebo Comparator
Arm Title
Placebo - Myelodysplastic Syndrome multi dose
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
SLN124
Intervention Description
SLN124 for subcutaneous (s.c.) injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Sodium chloride for s.c. injection
Primary Outcome Measure Information:
Title
Incidence of treatment-emergent adverse events
Description
safety and tolerability will be reported separately following single-dose administration.
Time Frame
Day 84
Title
Incidence of treatment-emergent adverse events
Description
safety and tolerability will be reported separately following multi-dose administration.
Time Frame
Day 140
Secondary Outcome Measure Information:
Title
Pharmacokinetic: peak plasma concentration (Cmax)
Description
Will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacokinetic: area under the plasma concentration (AUC)
Description
Will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacokinetic: apparent total clearance from plasma after s.c injection (CL/F)
Description
Will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacodynamic biomarkers: Change in TSAT after s.c injection.
Description
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacodynamic biomarkers: Change in hepcidin after s.c injection.
Description
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacodynamic biomarkers: Change in serum iron after s.c injection.
Description
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140
Title
Pharmacodynamic biomarkers: Change in haemoglobin after s.c injection.
Description
safety and tolerability will be reported separately following single-dose and multiple-dose administration.
Time Frame
Day 84 and Day 140

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult with alpha- or beta-thalassaemia or compound heterozygous haemoglobin E/beta-thalassaemia or adult with very low- or low-risk MDS according to the 2016 revision to the World Health Organisation classification. All subjects must agree to adhere to appropriate contraception requirements. Subjects must provide written informed consent and be able to comply with all study requirements. Body mass index ≥18 kg/m2 and ≤35 kg/m2 at screening. At least one of: a) Mean ferritin >250 μg/L based on a minimum of 2 measurements ≥1 week apart within 20 days before the planned dosing day, in the absence of active significant infection; b) Mean TSAT >40% measured on a minimum of 2 occasions ≥1 week apart within 20 days before the planned dosing day; c) Liver iron >3 mg Fe/g dry weight, measured according to local procedures. Mean baseline haemoglobin concentration ≥5 g/dL and ≤11 g/dL, based on a minimum of 2 measurements ≥1 week apart, within 20 days before the planned dosing day. Exclusion criteria Adult with haemoglobin S/alpha-thalassaemia or haemoglobin S/beta-thalassaemia or adult with secondary MDS, i.e., MDS that is known to have arisen because of chemical injury or treatment with chemotherapy and/or radiation for another disease. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc, or intolerance to s.c. injections. Known infection with HIV, or active infectious hepatitis A, B, or C virus. Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrolment in the study or could interfere with the subject's participation in, or completion of the study. History or clinical evidence of alcohol or illegal drug misuse within 2 years before screening. Currently using ESA, or plan to use ESA at any point during the study. Require daily treatment with 1 or more non-steroidal anti-inflammatory drugs during the study period. Paracetamol will be permitted for use as an antipyretic and/or analgesic. Treatment, or change in treatment with prohibited medications as specified in the protocol Treatment with ICT where the subject has not been on a stable dose for at least 8 weeks before screening or it is planned to initiate ICT therapy during the study. Clinically significant cardiac disease Clinically significant pulmonary disease For subjects with thalassaemia: Treatment, or change in treatment with prohibited medications as specified in the protocol currently and anticipated to receiving more than 5 units of RBCs during the 24 weeks to 6 weeks period before first dose of study drug. For subjects with very low / low-risk MDS: Previous allogeneic or autologous stem cell transplantation. Currently or planned to receive treatment with a corticosteroid for MDS within 8 weeks before screening. Currently or planned to receive treatment with haematopoietic growth factors (e.g., eltrombopag, romiplostim) within 8 weeks before screening.
Facility Information:
Facility Name
Universitaetsklinikum Duesseldorf
City
Düsseldorf
Country
Germany
Facility Name
Universitat Leipzig
City
Leipzig
Country
Germany
Facility Name
Rambam Health Care Campus
City
Haifa
Country
Israel
Facility Name
Sheba Medical Center
City
Ramat Gan
Country
Israel
Facility Name
Tel Aviv Sourasky Medical Center
City
Tel Aviv
Country
Israel
Facility Name
Bar-Ilan University - Faculty of Medicine
City
Zefat
Country
Israel
Facility Name
AUSL della Romagna - Ospedale di Ravenna
City
Ravenna
Country
Italy
Facility Name
Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia
City
Reggio Emilia
Country
Italy
Facility Name
Jordan University Hospital
City
Amman
Country
Jordan
Facility Name
King Hussein Cancer Center
City
Amman
Country
Jordan
Facility Name
Irbid Speciality Hospital
City
Irbid
Country
Jordan
Facility Name
Sarawak General Hospital
City
Kampung Sarawak
Country
Malaysia
Facility Name
Hospital Ampang
City
Kampung Selangor
Country
Malaysia
Facility Name
King Chulalongkorn Memorial Hospital
City
Bangkok
Country
Thailand
Facility Name
Mahidol University - Faculty of Medicine - Ramathibodi Hospital
City
Bangkok
Country
Thailand
Facility Name
Mahidol University - Siriraj Hospital
City
Bangkok
Country
Thailand
Facility Name
Faculty of Medicine, Chiang Mai University
City
Chiang Mai
Country
Thailand
Facility Name
University Hospital of Wales
City
Cardiff
Country
United Kingdom
Facility Name
The Leeds Teaching Hospitals NHS Trust - Saint James's University Hospital
City
Leeds
Country
United Kingdom
Facility Name
Hammersmith Medicines Research Ltd (HMR)
City
London
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

A Study Investigate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Response of SLN124 in Adults With Alpha/Beta-thalassaemia and Very Low- and Low-risk Myelodysplastic Syndrome

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